New studies by National Institute of Allergy and Infectious Diseases (NIAID)
scientists and grantees help fill in pieces of the AIDS vaccine research
puzzle. In three separate reports published in the February 1999 issue of
the journal Nature Medicine, researchers report new insights about the kind
of immune responses needed to protect against HIV infection. In the same
issue, another group presents important findings regarding the safety of
live, attenuated HIV vaccines.

The Role of Neutralizing Antibodies

Defining the precise immune responses that a vaccine must induce to protect
against infection with HIV will allow scientists to design tailor-made
vaccines that elicit those responses. Two series of experiments led by
Malcolm A. Martin, M.D., chief of NIAID's Laboratory of Molecular
Microbiology, provide important new information about the role that
antibodies can play in defending against HIV.

In one study, Dr. Martin and his colleagues showed that "neutralizing"
antibodies against HIV can prevent infection in primates. As their name
implies, neutralizing antibodies bind to the virus in a way that prevents it
from infecting cells. Dr. Martin's team isolated high levels of very potent
neutralizing antibodies from healthy but HIV-infected chimpanzees and
transferred them to rhesus monkeys. The monkeys were then exposed to SHIV,
a hybrid virus composed of a simian immunodeficiency virus (SIV) core
surrounded by HIV envelope proteins. SHIV normally causes infection in
primates. However, none of the monkeys that had been passively immunized
with the neutralizing antibodies became infected with SHIV.

In a second study, conducted with scientists from the National Cancer
Institute, Dr. Martin's research team investigated whether neutralizing
antibodies to HIV can accelerate the removal of HIV from the blood of
monkeys. The scientists measured HIV clearance after infusing large
quantities of the virus into three groups of monkeys: animals that had been
persistently infected with SHIV for several years (and therefore made
antibodies that recognized the HIV proteins); uninfected animals that had
received the anti-HIV antibodies as in the first study; and animals that had
never been infected with HIV or SHIV.

The researchers found that HIV rapidly disappeared from the blood in each
group of animals. However, in monkeys with neutralizing antibodies to HIV,
virus clearance occurred more than twice as fast as in animals lacking
these antibodies.

Dr. Martin acknowledges that scientists do not yet know how to elicit
neutralizing antibodies to HIV in humans, nor can they produce antibodies
that will cross-react broadly with different strains of HIV. He also notes
that an effective preventive vaccine against HIV may have to elicit multiple
immune responses that can interfere with different steps in the HIV life
cycle. Still, Dr. Martin's demonstration that neutralizing antibodies can
prevent HIV infection should be a boon to HIV vaccine research.

"If we can learn how to raise sufficient quantities of neutralizing
antibodies to a broad range of HIV strains, we will have made an important
step towards an effective HIV vaccine."

Broad-Based Immunity Essential in Mice

A study by another team of NIAID researchers suggests that HIV vaccines must
elicit responses in all three major immune cell subsets - antibody producing
B cells, CD4+ (helper) T cells, and CD8+ (killer) T cells - to be effective.

Kim J. Hasenkrug, Ph.D., of NIAID's Rocky Mountain Laboratories in Hamilton,
Mont., and his colleague Ulf Dittmer, Ph.D., immunized mice with a live,
attenuated vaccine against Friend virus, a retrovirus that causes a fatal,
immunosuppressive disease in mice. The vaccine they used is highly
effective at preventing disease. To determine which immune responses confer
protection, they transferred various combinations of all three major immune
cell subsets from immunized mice to non-immunized mice, then exposed the
mice to a pathogenic form of Friend virus.

The researchers found that mice that had received just one or two immune
cell types became infected and developed disease. Only mice that received
all three immune cell types were completely protected from infection with
the virus.

"Each lymphocyte subset seems to have unique and necessary functions that
act in concert to induce protection," notes Dr. Hasenkrug. "It remains
possible that single or dual lymphocyte subsets might be protective if
transferred in overwhelming numbers, but the efficacy of vaccination with
live, attenuated Friend virus seems to be related to its ability to
stimulate multiple arms of the immune system. The implication is that only
broadly based HIV vaccines that are designed to elicit responses in all
three types of immune cells will prove effective."

Live, Attenuated Vaccines - How Safe?

Some scientists believe that a live, attenuated HIV vaccine - composed of
virus rendered non-pathogenic by removal of one or more essential genes -
could be the best way to stimulate broad-based immunity to HIV. Other
scientists, however, question whether concerns about the safety of using
live, attenuated HIV vaccines can be adequately addressed. Given HIV's
propensity to mutate, they fear that an attenuated strain of HIV could
revert to a pathogenic form.

Researchers led by NIAID grantee Ruth Ruprecht, M.D., Ph.D., of the
Dana-Farber Cancer Institute in Boston, in collaboration with scientists at
the Yerkes Regional Primate Research Center in Atlanta, report that an
experimental live, attenuated SIV vaccine can cause AIDS in infant and adult
monkeys. The vaccine consisted of an SIV strain from which three different
genetic elements, each involved in viral replication, had been removed.

"Our findings confirm that this triply deleted SIV candidate vaccine retains
its ability to cause AIDS," says Dr. Ruprecht. "Given the genetic
similarities between HIV and SIV, a live, attenuated virus vaccine based on
attenuation of replicative capacity should not be considered as a candidate
for a human AIDS vaccine." Rather, she adds, attenuation strategies should
focus on identifying viral genes that control virulence.

NIAID is a component of the National Institutes of Health (NIH). NIAID
conducts and supports research to prevent, diagnose and treat illnesses such
as HIV disease and other sexually transmitted diseases, tuberculosis,
malaria, asthma and allergies. NIH is an agency of the U.S. Department of
Health and Human Services.

Press releases, fact sheets and other NIAID-related materials are available
on the NIAID Web site at http://www.niaid.nih.gov.